PROJECTSUMMARY The overarching goal of this project is to better understand the links between ASD genetic risk, resulting distributedbrainconnectivityimpairments,andtheimpactofthisonASD-relevantbehaviors.Wewilldothisby performingstate-of-theartinvivoelectrophysiologystudiesinawake-behavinganimalsthatmodelamonogenic formofASD.Thisresearchprojectissignificantbecausealteredbrainconnectivityisroutinelyobserved in ASD patients, though it remains unknown how brain connectivity alterations cause abnormal behaviorsrelevanttoASD.Intheanimalmodel,wewillfocusonbehaviorsthatoptimizeactivetouch.Thisis approach is valid because altered sensory function, including touch, is a core manifestation of ASD and somatomotorbrainareasdisplayalteredactivationinASDpatients.Anemergingideaisthatalteredfunctioning of sensory systems directly impairs the functions of other major neural domains, such as cognitive and social systems.Activetoucharisesthroughrapidadaptionsinthedynamicsoftouchorgansinresponsetophysical contact with objects. This behavioral transformation optimizes touch-related input into the brain and is an emergent behavior resulting from sensorimotor integration at various levels in the nervous system. Therefore, wegenerallyhypothesizethatgeneticvariantsthatcauseASDdisruptkeypointsoffunctionalconnectivitywithin the somatomotor system, which in turncauses altered activetouch behaviors, leading toaltered acquisitionof tactileinformation.Thishypothesisissignificantbecauseitcoulddefineaneuralprocess(i.e.altereddistributed functional connectivity) that explains how sensory-guided adaptive behaviors are impaired by genetic variants thatcauseASD.Ourmodelingstudiesalsohavethepotentialtodefinehowalteredbrainconnectivitycandisrupt relevant behaviors. We will test this hypothesis in the first aim by recording the flow of information throughout themajorareasofthesomato-motorsysteminamousemodelforamonogenicformofASD.Theproposedin vivo recordings in awake-behaving animals will utilize state-of-art silicon neural probes that will enable us to measurelocalandlong-rangefunctionalconnectivityofneuronsduringdistinctbehaviors,includingduringactive touchesofobjects.Thesesophisticatedmeasurementswillidentifycircuitsthatarefunctionallyimpairedduring ASD-relevant behaviors. The second aim takes a distinct, but complementary approach by regionally and temporallydisruptingexpressionofthecausalASDgeneandthenobservingtheimpactoftheseperturbations onbehaviorsthatdefineetiologically-relevantactivetouch.WeexpecttofindthatproperexpressionoftheASD gene is required in developing somatomotor cortical areas to promote normal active touch behaviors. The combinedimpactofthesecomplementaryapproachesisthattheyareexpectedtodefinethecircuitsthatcause abnormal active touch-related behaviors in the mouse model. Thus, the proposed research is expected to advanceourunderstandingofhowmajorASDriskgenesdisrupttheconnectivityofneuralcircuitsthatunderlie relevantbehaviors.